The diagnosis of Parkinson’s disease (PD) and atypical parkinsonian syndromes is difficult due to the lack of reliable, easily accessible biomarkers. Multiple system atrophy (MSA) is a synucleinopathy whose symptoms often overlap with PD. Exosomes isolated from blood by immunoprecipitation using CNS markers provide a window into the brain’s biochemistry and may assist in distinguishing between PD and MSA. Thus, we asked whether α-synuclein (α-syn) in such exosomes could distinguish among healthy individuals, patients with PD, and patients with MSA. We isolated exosomes from the serum or plasma of these three groups by immunoprecipitation using neuronal and oligodendroglial markers in two independent cohorts and measured α-syn in these exosomes using an electrochemiluminescence ELISA. In both cohorts, α-syn concentrations were significantly lower in the control group and significantly higher in the MSA group compared to the PD group. The ratio between α-syn concentrations in putative oligodendroglial exosomes compared to putative neuronal exosomes was a particularly sensitive biomarker for distinguishing between PD and MSA. Combining this ratio with the α-syn concentration itself and the total exosome concentration, a multinomial logistic model trained on the discovery cohort separated PD from MSA with an AUC = 0.902, corresponding to 89.8% sensitivity and 86.0% specificity when applied to the independent validation cohort. The data demonstrate that a minimally invasive blood test measuring α-syn in blood exosomes immunoprecipitated using CNS markers can distinguish between patients with PD and patients with MSA with high sensitivity and specificity. Future optimization and validation of the data by other groups would allow this strategy to become a viable diagnostic test for synucleinopathies.
BackgroundSeveral articles suggest that DNA methylation levels in blood relate to Parkinson’s disease (PD) but there is a need for a large-scale study that involves suitable population based controls. The purposes of the study were: (1) to study whether PD status is associated with DNA methylation levels in blood/saliva; (2) to study whether observed associations relate to blood cell types; and (3) to characterize genome-wide significant markers (“CpGs”) and clusters of CpGs (co-methylation modules) in terms of biological pathways.MethodsIn a population-based case control study of PD, we studied blood samples from 335 PD cases and 237 controls and saliva samples from another 128 cases and 131 controls. DNA methylation data were generated from over 486,000 CpGs using the Illumina Infinium array. We identified modules of CpGs (clusters) using weighted correlation network analysis (WGCNA).ResultsOur cross-sectional analysis of blood identified 82 genome-wide significant CpGs (including cg02489202 in LARS2 p = 8.3 × 10–11 and cg04772575 in ABCB9 p = 4.3 × 10–10). Three out of six PD related co-methylation modules in blood were significantly enriched with immune system related genes. Our analysis of saliva identified five significant CpGs. PD-related CpGs are located near genes that relate to mitochondrial function, neuronal projection, cytoskeleton organization, systemic immune response, and iron handling.ConclusionsThis study demonstrates that: (1) PD status has a profound association with DNA methylation levels in blood and saliva; and (2) the most significant PD-related changes reflect changes in blood cell composition. Overall, this study highlights the role of the immune system in PD etiology but future research will need to address the causal structure of these relationships.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0466-5) contains supplementary material, which is available to authorized users.
Background: Lifestyle factors may contribute to the development of Parkinson’s disease, but little is known about factors that influence progression. The objective of the current study was to examine whether caffeine or alcohol consumption, physical activity, or cigarette smoking is associated with progression and survival among PD patients. Methods: We assessed lifelong coffee, tea, and alcohol consumption, smoking, and physical activity in a prospective community-based cohort (n = 360). All patients were passively followed for mortality (2001–2016); 244 were actively followed on average ± SD 5.3 ± 2.1 years (2007–2014). Movement disorder specialists repeatedly assessed motor function (Hoehn & Yahr) and cognition (Mini-Mental State Exam). We used Cox proportional hazards models and inverse probability weights to account for censoring. Results: Coffee, caffeinated tea, moderate alcohol consumption, and physical activity were protective against at least 1 outcome. Smoking and heavy alcohol consumption were associated with increased risks. Coffee was protective against time to Hoehn & Yahr stage 3 (hazard ratio, 0.52; 95% confidence interval, 0.28–1.01), cognitive decline (hazard ratio, 0.23; 95% confidence interval, 0.11,0.48), and mortality (hazard ratio, 0.47; 95% confidence interval, 0.32–0.69). Relative to moderate drinkers, those who never drank liquor and those who drank more heavily were at an increased risk of Hoehn & Yahr 3 (hazard ratio, 3.48; 95% confidence interval, 1.90–6.38; and hazard ratio, 2.16; 95% confidence interval, 1.03, 4.54, respectively). A history of competitive sports was protective against cognitive decline (hazard ratio, 0.46; 95% confidence interval, 0.22–0.96) and Hoehn & Yahr 3 (hazard ratio, 0.42; 95% confidence interval, 0.23–0.79), as was physical activity measured by metabolic-equivalent hours. Current cigarette smoking was associated with faster cognitive decline (hazard ratio, 3.20; 95% confidence interval, 1.02–10.01). Conclusions: This population-based study suggests that lifestyle factors influence PD progression and mortality.
IMPORTANCE Genetic factors have a well-known influence on Parkinson disease (PD) susceptibility. The largest genome-wide association study (GWAS) identified 26 independent single-nucleotide polymorphisms (SNPs) associated with PD risk. Among patients, the course and severity of symptom progression is variable, and little is known about the potential association of genetic factors with phenotypic variance. OBJECTIVE To assess whether GWAS-identified PD risk SNPs also have a cumulative association with the progression of cognitive and motor symptoms in patients with PD. DESIGN, SETTING, AND PARTICIPANTS This longitudinal population-based cohort study of 285 patients of European ancestry with incident PD genotyped 23 GWAS SNPs. One hundred ninety-nine patients were followed up for a mean (SD) of 5.3 (2.1) years for progression
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